Therapy For Peripheral Nerve Injury Research Articles

Biological characteristics of tissue engineered-nerve grafts enhancing peripheral nerve regeneration

BackgroundA favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA).MethodsIn order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein–protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively.ResultsThe results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1β and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-β, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences.ConclusionsThis study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation.

Interactions between Schwann cell and extracellular matrix in peripheral nerve regeneration.

Peripheral nerve injuries, caused by various reasons, often lead to severe sensory, motor, and autonomic dysfunction or permanent disability, posing a challenging problem in regenerative medicine. Autologous nerve transplantation has been the gold standard in traditional treatments but faces numerous limitations and risk factors, such as donor area denervation, increased surgical complications, and diameter or nerve bundle mismatches. The extracellular matrix (ECM) is a complex molecular network synthesized and released into the extracellular space by cells residing in tissues or organs. Its main components include collagen, proteoglycans/glycosaminoglycans, elastin, laminin, fibronectin, etc., providing structural and biochemical support to surrounding cells, crucial for cell survival and growth. Schwann cells, as the primary glial cells in the peripheral nervous system, play various important roles. Schwann cell transplantation is considered the gold standard in cell therapy for peripheral nerve injuries, making ECM derived from Schwann cells one of the most suitable biomaterials for peripheral nerve repair. To better understand the mechanisms of Schwann cells and the ECM in peripheral nerve regeneration and their optimal application, this review provides an overview of their roles in peripheral nerve regeneration.

Inhibition of Schwann Cell Pyroptosis Promotes Nerve Regeneration in Peripheral Nerve Injury in Rats.

Peripheral nerve injury (PNI) is one of the most debilitating injuries, but therapies for PNI are still far from satisfactory. Pyroptosis, a recently identified form of cell death, has been demonstrated to participate in different diseases. However, the role of pyroptosis of Schwann cells in PNI remains unclear. We established a rat PNI model, and western blotting, transmission electron microscopy, and immunofluorescence staining were used to confirm pyroptosis of Schwann cells in PNI in vivo. In vitro, pyroptosis of Schwann cells was induced by lipopolysaccharides (LPS)+adenosine triphosphate disodium (ATP). An irreversible inhibitor of pyroptosis, acetyl (Ac)-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-cmk), was used to attenuate Schwann cell pyroptosis. Moreover, the influence of pyroptotic Schwann cells on the function of dorsal root ganglion neurons (DRGns) was analyzed by a coculture system. Finally, the rat PNI model was intraperitoneally treated with Ac-YVAD-cmk to observe the effect of pyroptosis on nerve regeneration and motor function. Schwann cell pyroptosis was notably observed in the injured sciatic nerve. LPS+ATP treatment effectively induced Schwann cell pyroptosis, which was largely attenuated by Ac-YVAD-cmk. Additionally, pyroptotic Schwann cells inhibited the function of DRGns by secreting inflammatory factors. A decrease in pyroptosis in Schwann cells promoted regeneration of the sciatic nerve and recovery of motor function in rats. Given the role of Schwann cell pyroptosis in PNI progression, inhibition of Schwann cell pyroptosis might be a potential therapeutic strategy for PNI in the future.

Electrical stimulation therapy for peripheral nerve injury.

Peripheral nerve injury is common and frequently occurs in extremity trauma patients. The motor and sensory impairment caused by the injury will affect patients' daily life and social work. Surgical therapeutic approaches don't assure functional recovery, which may lead to neuronal atrophy and hinder accelerated regeneration. Rehabilitation is a necessary stage for patients to recover better. A meaningful role in non-pharmacological intervention is played by rehabilitation, through individualized electrical stimulation therapy. Clinical studies have shown that electrical stimulation enhances axon growth during nerve repair and accelerates sensorimotor recovery. According to different effects and parameters, electrical stimulation can be divided into neuromuscular, transcutaneous, and functional electrical stimulation. The therapeutic mechanism of electrical stimulation may be to reduce muscle atrophy and promote muscle reinnervation by increasing the expression of structural protective proteins and neurotrophic factors. Meanwhile, it can modulate sensory feedback and reduce neuralgia by inhibiting the descending pathway. However, there are not many summary clinical application parameters of electrical stimulation, and the long-term effectiveness and safety also need to be further explored. This article aims to explore application methodologies for effective electrical stimulation in the rehabilitation of peripheral nerve injury, with simultaneous consideration for fundamental principles of electrical stimulation and the latest technology. The highlight of this paper is to identify the most appropriate stimulation parameters (frequency, intensity, duration) to achieve efficacious electrical stimulation in the rehabilitation of peripheral nerve injury.

Sciatic nerve injury regeneration in adult male rats using gelatin methacrylate (GelMA)/poly(2-ethy-2-oxazoline) (PEtOx) hydrogel containing 4-aminopyridine (4-AP).

One of the most important parts of the body is the peripheral nervous system, and any injuries in this system may result in potentially lethal consequences or severe side effects. The peripheral nervous system may not rehabilitate the harmed regions following disabling disorders, which reduce the quality of life of patients. Fortunately, in recent years, hydrogels have been proposed as exogenous alternatives to bridge damaged nerve stumps to create a useful microenvironment for advancing nerve recovery. However, hydrogel-based medicine in the therapy of peripheral nerve injury still needs a lot of improvement. In this study, GelMA/PEtOx hydrogel was used for the first time to deliver 4-Aminopyridine (4-AP) small molecules. 4-AP is a broad-spectrum potassium channel blocker, which has been demonstrated to increase neuromuscular function in patients with various demyelinating disorders. The prepared hydrogel showed a porosity of 92.2± 2.6% after 20 min, swelling ratio of 456.01 ± 2.0% after 180 min, weight loss of 81.7± 3.1% after 2 weeks, and good blood compatibility as well as sustainable drug release. MTT analysis was performed to assess the cell viability of the hydrogel and proved that the hydrogel is an appropriate substrate for the survival of cells. In vivo studies were performed for functional analysis and the sciatic functional index (SFI) as well as hot plate latency results showed that the use of GelMA/PEtOx+4-AP hydrogel enhances the regeneration compared to the GelMA/PEtOx hydrogel and the control group.

S-Propargyl-Cysteine Ameliorates Peripheral Nerve Injury through Microvascular Reconstruction

Microvascular reconstruction is essential for peripheral nerve repair. S-Propargyl-cysteine (SPRC), the endogenous hydrogen sulfide (H2S) donor, has been reported to promote angiogenesis. The aim of this study is to utilize the pro-angiogenic ability of SPRC to support peripheral nerve repair and to explore the potential mechanisms. The effects and mechanisms of SPRC on angiogenesis and peripheral nerve repair were examined under hypoxic condition by establishing a sciatic nerve crushed injury model in mice and rats, and a hypoxia model in human umbilical vascular endothelial cells (HUVECs) in vitro. We found that SPRC accelerated the function recovery of the injured sciatic nerve and alleviated atrophy of the gastrocnemius muscle in mice. It facilitated the viability of Schwann cells (SCs), the outgrowth and myelination of regenerated axons, and angiogenesis in rats. It enhanced the viability, proliferation, adhesion, migration, and tube formation of HUVECs under hypoxic condition. SPRC activated sirtuin1 (SIRT1) expression by promoting the production of endogenous H2S, and SIRT1 negatively regulated Notch signaling in endothelial cells (ECs), thereby promoting angiogenesis. Collectively, our study has provided important evidence that SPRC has an effective role in peripheral nerve repair through microvascular reconstruction, which could be a potentially effective medical therapy for peripheral nerve injury.

The Healing Effect Of Digoxin On Peripheral Nerve Damage and Its Relation to IL-17/IL-10.

Peripheral nerve damage mainly develops after mechanical trauma, and microenvironment impairment after damage delays the healing process. Additionally, digoxin is a glycoside with proven anti-inflammatory activity. Thus, this study aimed to demonstrate the curative effect of digoxin on peripheral nerve damage with its anti-inflammatory role on interleukin (IL)-17. The study was conducted with 30 male Sprague Dawley albino mature rats, of which 10 formed the control group, 10 were surgically treated and administered saline (group S), and another 10 were surgically treated and administered digoxin (group D). Motor functions and immunohistochemical and biochemical variables of the rats were assessed after therapy. The amplitude of the inclined plane test scores and the compound muscle action potential levels were greater in group D than in group S. Likewise, there were higher nerve growth factor percentages, higher axon counts, and lower fibrosis score percentages in group D than is group S. Lastly, lower tissue malondialdehyde and plasma IL-17 levels were determined in group D, while the IL-10 level was higher. Digoxin contributes to nerve healing and neuroprotective effect by demonstrating its anti-inflammatory effect on IL-17. It can be considered an adjunctive therapy for peripheral nerve injury.

Mature but not developing Schwann cells promote axon regeneration after peripheral nerve injury

Since Schwann cells (SCs) support axonal growth at development as well as after peripheral nerve injury (PNI), developing SCs might be able to promote axon regeneration after PNI. The purpose of the current study was to elucidate the capability of developing SCs to induce axon regeneration after PNI. SC precursors (SCPs), immature SCs (ISCs), repair SCs (RSCs) from injured nerves, and non-RSCs from intact nerves were tested by grafting into acellular region of rat sciatic nerve with crush injury. Both of developing SCs completely failed to support axon regeneration, whereas both of mature SCs, especially RSCs, induced axon regeneration. Further, RSCs but not SCPs promoted neurite outgrowth of adult dorsal root ganglion neurons. Transcriptome analysis revealed that the gene expression profiles were distinctly different between RSCs and SCPs. These findings indicate that developing SCs are markedly different from mature SCs in terms of functional and molecular aspects and that RSC is a viable candidate for regenerative cell therapy for PNI.

Transplanted neural lineage cells derived from dental pulp stem cells promote peripheral nerve regeneration.

Cell therapy for peripheral nerve injury is a promising strategy as regenerative medicine that restores neurological function. However, challenges remain in producing suitable and sufficient amounts of autologous cells for promoting nerve regeneration. This study aimed to identify the characteristics of neural lineage cells (NLCs) differentiated from dental pulp stem cells (DPSCs) and reveal their effect on functional recovery and nerve regeneration after cell transplantation into an immunodeficient rat using a nerve guide conduit. Here we report a protocol of neural induction in monolayer culture and characterize NLCs in vitro. Furthermore, NLCs were transplanted into an immunodeficient rat model with a 10-mm sciatic nerve defect, and cell survival and differentiation were investigated in vivo. Outcomes of nerve regeneration were also assessed using the remyelinated axon numbers, myelin sheath thickness, electrophysiological activities, and gastrocnemius muscle mass. NLCs comprised neuronal, astrocyte, oligodendrocyte, and neural crest lineage cells. NLCs enhanced the activities of endothelial cells, Schwann cells, and neurons in a paracrine-dependent manner in vitro. At 2weeks post-transplantation, numerous transplanted NLCs differentiated into platelet-derived growth factor receptor alpha (PDGFRα) + oligodendrocyte progenitor cells (OPCs) and a few PDGFRα + /p75 neurotrophin receptor + Schwann cell-like cells derived from OPCs were observed. At 12weeks post-transplantation, human Schwann cell-like cells survived, and axon growth, remyelination, electrophysiological activities, and muscle atrophy were improved. This study demonstrates the broad application of our protocol of neural induction of DPSCs and portrays the efficacy of transplantation of NLCs derived from human DPSCs as a promising strategy for peripheral nerve regeneration.

ALK5 i II Accelerates Induction of Adipose-Derived Stem Cells toward Schwann Cells through a Non-Smad Signaling Pathway.

Schwann cells (SCs) are likely to be a vital component of cell-based therapies for nerve regeneration. There are various methods for inducing SC-like cells (SCLCs) from adipose-derived stem cells (ADSCs), but their phenotypic and functional characteristics remain unsatisfactory. Here, we report a novel efficient procedure to induce SCLCs by culturing ADSCs with ALK5 inhibitor (ALK5 i) II, a specific inhibitor of activin-like kinase 5 (ALK5) (transforming growth factor-β receptor 1 (TGFβR1)) that is also known as Repsox. The resultant cells that we named “modified SCLCs (mSCLCs)” expressed SC-specific genes more strongly than conventional SCLCs (cSCLCs) and displayed a neurosupportive capacity in vitro, similarly to genuine SCs. Regarding the mechanism of the mSCLC induction by ALK5 i II, knockdown of Smad2 and Smad3, key proteins in the TGFβ/Smad signaling pathway, did not induce SC markers. Meanwhile, expression of multipotent stem cell markers such as Sex-determining region Y- (SRY-) box 2 (Sox2) was upregulated during induction. These findings imply that ALK5 i II exerts its effect via the non-Smad pathway and following upregulation of undifferentiated cell-related genes such as Sox2. The procedure described here results in highly efficient induction of ADSCs into transgene-free and highly functional SCLCs. This approach might be applicable to regeneration therapy for peripheral nerve injury.

Long-term survival of transplanted induced pluripotent stem cell-derived neurospheres with nerve conduit into sciatic nerve defects in immunosuppressed mice

Since the advent of induced pluripotent stem cells (iPSCs), clinical trials using iPSC-based cell transplantation therapy have been performed in various fields of regenerative medicine. We previously demonstrated that the transplantation of mouse iPSC-derived neurospheres containing neural stem/progenitor cells with bioabsorbable nerve conduits promoted nerve regeneration in the long term in murine sciatic nerve defect models. However, it remains unclear how long the grafted iPSC-derived neurospheres survived and worked after implantation. In this study, the long-term survival of the transplanted mouse iPSC-derived neurospheres with nerve conduits was evaluated in high-immunosuppressed or non-immunosuppressed mice using in vivo imaging for the development of iPSC-based cell therapy for peripheral nerve injury. Complete 5-mm long defects were created in the sciatic nerves of immunosuppressed and non-immunosuppressed mice and reconstructed using nerve conduits coated with iPSC-derived neurospheres labeled with ffLuc. The survival of mouse iPSC-derived neurospheres on nerve conduits was monitored using in vivo imaging. The transplanted iPSC-derived neurospheres with nerve conduits survived for 365 days after transplantation in the immunosuppressed allograft models, but only survived for at least 14 days in non-immunosuppressed allograft models. This is the first study to find the longest survival rate of stem cells with nerve conduits transplanted into the peripheral nerve defects using in vivo imaging and demonstrates the differences in graft survival rate between the immunosuppressed allograft model and immune responsive allograft model. In the future, if iPSC-derived neurospheres are successfully transplanted into peripheral nerve defects with nerve conduits using iPSC stock cells without eliciting an immune response, axonal regeneration will be induced due to the longstanding supportive effect of grafted cells on direct remyelination and/or secretion of trophic factors.

Improvement of sensory neuron growth and survival via negatively regulating PTEN by miR-21-5p-contained small extracellular vesicles from skin precursor-derived Schwann cells

BackgroundPatients with peripheral nerve injury (PNI) often suffer from hypoxic ischemic impairments, in particular when combined with vascular damage, causing neuronal dysfunction and death. Increasing attention has been paid on skin precursor-derived Schwann cells (SKP-SCs), and previous study has shown that SKP-SCs could promote sensory recovery after cell therapy for PNI, resembling the effect of naive SCs, and SKP-SC-derived extracellular vesicles (SKP-SC-EVs) are putatively supposed to be promising therapeutic agents for neural regeneration.MethodsSKPs were induced to differentiate towards SCs with cocktail factors (N2, neuregulin-1β, and forskolin) in vitro. SKP-SC-EVs were isolated by exoEasy Maxi Kit and characterized by morphology and phenotypic markers of EVs. Rat sensory neurons from dorsal root ganglions (DRGs) were primarily cultured in regular condition or exposed to oxygen-glucose-deprivation (OGD) condition. SKP-SC-EVs were applied to DRGs or sensory neurons, with LY294002 (a PI3K inhibitor) added; the effect on neurite outgrowth and cell survival was observed. Moreover, microRNA (miR) candidate contained in SKP-SC-EVs was screened out, and miR-mimics were transfected into DRG neurons; meanwhile, the negative regulation of PTEN/PI3K/Akt axis and downstream signaling molecules were determined.ResultsIt was shown that SKP-SC-EVs could improve the neurite outgrowth of DRGs and sensory neurons. Furthermore, SKP-SC-EVs enhanced the survival of sensory neurons after OGD exposure by alleviating neuronal apoptosis and strengthening cell viability, and the expression of GAP43 (a neuron functional protein) in neurons was upregulated. Moreover, the neuro-reparative role of SKP-SC-EVs was implicated in the activation of PI3K/Akt, mTOR, and p70S6k, as well as the reduction of Bax/Bcl-2 ratio, that was compromised by LY294002 to some extent. In addition, transferring miR-21-5p mimics into sensory neurons could partly protect them from OGD-induced impairment.ConclusionsSum up, SKP-SC-EVs could improve neurite outgrowth of DRG sensory neurons in physiological and pathological condition. Moreover, the in vitro therapeutic potential of SKP-SC-EVs on the survival and restoration of OGD-injured sensory neurons was evidenced to be associated with miR-21-5p contained in the small EVs and miR-21-5p/PTEN/PI3K/Akt axis.Graphic abstract

Cortical plasticity and nerve regeneration after peripheral nerve injury.

With the development of neuroscience, substantial advances have been achieved in peripheral nerve regeneration over the past decades. However, peripheral nerve injury remains a critical public health problem because of the subsequent impairment or absence of sensorimotor function. Uncomfortable complications of peripheral nerve injury, such as chronic pain, can also cause problems for families and society. A number of studies have demonstrated that the proper functioning of the nervous system depends not only on a complete connection from the central nervous system to the surrounding targets at an anatomical level, but also on the continuous bilateral communication between the two. After peripheral nerve injury, the interruption of afferent and efferent signals can cause complex pathophysiological changes, including neurochemical alterations, modifications in the adaptability of excitatory and inhibitory neurons, and the reorganization of somatosensory and motor regions. This review discusses the close relationship between the cerebral cortex and peripheral nerves. We also focus on common therapies for peripheral nerve injury and summarize their potential mechanisms in relation to cortical plasticity. It has been suggested that cortical plasticity may be important for improving functional recovery after peripheral nerve damage. Further understanding of the potential common mechanisms between cortical reorganization and nerve injury will help to elucidate the pathophysiological processes of nerve injury, and may allow for the reduction of adverse consequences during peripheral nerve injury recovery. We also review the role that regulating reorganization mechanisms plays in functional recovery, and conclude with a suggestion to target cortical plasticity along with therapeutic interventions to promote peripheral nerve injury recovery.

Mechanical, topographicaland chemical cues combined with physical therapy for peripheral nerve injuries.

Aim: The aim of this paper is to evaluate biomaterial cues combined with physical therapy (PT) on functional recovery in a rat sciatic nerve injury model. Materials & methods: Nerve growth conduits were filled with longitudinally aligned hyaluronic acid fibers and microspheres containing neurotrophic factor (growth factor[GF]). All animals received behavior and functional testing throughout the study, which concluded with measurement of compound muscle action potentials and contractile force of the gastrocnemius muscle. Results & conclusion: Including GF improved recovery of gross motor function and increased sensory pain sensation. During the 4weeks that animals participated in PT, these groups showed higher static sciatic index scores. Including GF and PT has the potential to improve clinical outcomes following peripheral nerve injury.

4-AP-3-MeOH Promotes Structural and Functional Spontaneous Recovery in the Acute Sciatic Nerve Stretch Injury

Background:4-AP-3-MeOH, a derivative of 4-aminopyridine, was developed and demonstrated to prevent nerve pulse diffusion due to myelin damage and significantly enhance axonal conduction following nerve injury. Currently, repurposing the existing drug such as 4-AP-3-MeOH to restore motor function is a promising and potential therapy of peripheral nerve injury. However, to evaluate drug effect on sciatic nerve injury is full of challenge.Methods:Sciatic functional index was used to determine and measure the walking track in the stretch injury model. Nerve conductivity was performed by electrical stimulation of a nerve and recording the compound muscle action potential. Myelin thickness and regeneration was imaged and measured with transmission electron microscopy (TEM).Results:In this study, we developed a sciatic nerve injury model to minimize the spontaneous recovery mechanism and found that 4-AP-3-MeOH not only improved walking ability of the animals but also reduced the sensitivity to thermal stimulus. More interesting, 4-AP-3-MeOH enhanced and recovered electric conductivity of injured nerve; our TEM results indicated that the axon sheath thickness was increased and myelin was regenerated, which was an important evidence to support the recovery of injured nerve conductivity with 4-AP-3-MeOH treatment.Conclusions:In summary, our studies suggest that 4-AP-3-MeOH is a viable and promising approach to the therapy of peripheral nerve injury and in support of repurposing the existing drug to restore motor function.

Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration.

Rationale: Autophagy in Schwann cells (SCs) is crucial for myelin debris degradation and clearance following peripheral nerve injury (PNI). Nerve growth factor (NGF) plays an important role in reconstructing peripheral nerve fibers and promoting axonal regeneration. However, it remains unclear if NGF effect in enhancing nerve regeneration is mediated through autophagic clearance of myelin debris in SCs.Methods: In vivo, free NGF solution plus with/without pharmacological inhibitors were administered to a rat sciatic nerve crush injury model. In vitro, the primary Schwann cells (SCs) and its cell line were cultured in normal medium containing NGF, their capable of swallowing or clearing degenerated myelin was evaluated through supplement of homogenized myelin fractions.Results: Administration of exogenous NGF could activate autophagy in dedifferentiated SCs, accelerate myelin debris clearance and phagocytosis, as well as promote axon and myelin regeneration at early stage of PNI. These NGF effects were effectively blocked by autophagy inhibitors. In addition, inhibition of the p75 kD neurotrophin receptor (p75NTR) signal or inactivation of the AMP-activated protein kinase (AMPK) also inhibited the NGF effect as well.Conclusions: NGF effect on promoting early nerve regeneration is closely associated with its accelerating autophagic clearance of myelin debris in SCs, which probably regulated by the p75NTR/AMPK/mTOR axis. Our studies thus provide strong support that NGF may serve as a powerful pharmacological therapy for peripheral nerve injuries.

Diffusional plasticity induced by electroacupuncture intervention in rat model of peripheral nerve injury

Electroacupuncture (EA) is an adjuvant therapy for peripheral nerve injury (PNI). Both peripheral and central alterations contribute to the rehabilitation process. We employed diffusion tensor imaging (DTI) to investigate the diffusion plasticity of afferent and efferent pathways caused by EA in model of peripheral nerve injury and reparation. Twenty-four rats were divided into three groups: normal group, model group and intervention group. Rats of the model group and the intervention group underwent sciatic nerve transection and anastomosis. EA intervention was performed on the intervention group at ST-36 and GB-30 for three months. Gait assessment and DTI were conducted at days post-operative (DPO) 30, 60 and 90. We selected corticospinal tract, spinothalamic tract and internal capsule as regions of interest and analyzed diffusion metrics including fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). FA values and RD values displayed significant differences or obvious tendency while AD values maintained a stable level. RD values displayed better indicative performance than FA in internal capsule. The intervention group presented significant correlation between RD values and Regularity Index (RI) during the intervention period. The effect of EA on peripheral nerve injury repairing rats appeared to be accelerated recovery process of sensory and motor neural pathway. We proposed that RD was a potential in vivo indicator for structural plasticity caused by EA and PNI.

MSC-Derived Exosomes-Based Therapy for Peripheral Nerve Injury: A Novel Therapeutic Strategy.

Although significant advances have been made in synthetic nerve conduits and surgical techniques, complete regeneration following peripheral nerve injury (PNI) remains far from optimized. The repair of PNI is a highly heterogeneous process involving changes in Schwann cell phenotypes, the activation of macrophages, and the reconstruction of the vascular network. At present, the efficacy of MSC-based therapeutic strategies for PNI can be attributed to paracrine secretion. Exosomes, as a product of paracrine secretion, are considered to be an important regulatory mediator. Furthermore, accumulating evidence has demonstrated that exosomes from mesenchymal stem cells (MSCs) can shuttle bioactive components (proteins, lipids, mRNA, miRNA, lncRNA, circRNA, and DNA) that participate in almost all of the abovementioned processes. Thus, MSC exosomes may represent a novel therapeutic tool for PNI. In this review, we discuss the current understanding of MSC exosomes related to peripheral nerve repair and provide insights for developing a cell-free MSC therapeutic strategy for PNI.

Mechanism of miR-148b inhibiting cell proliferation and migration of Schwann cells by regulating CALR

The aim of this study is to investigate the effect of miR-148b on cell proliferation and migration of Schwann cells and explore its mechanism. The miR-148b group, miR-con group and the anti-miR-148b group, anti-miR-con group, si-con group, si-CALR group, Ctrl group, CALR group were transfected into Schwann cells by liposome method; the expression of miR-148b was detected by qRT-PCR; the cell viability was detected by MTT assay; the migration of cells was detected by Transwell method; WB assay was used to detect the protein expression of CALR. Firstly, we found that compared with miR-con group and si-con group, the proliferation and migration of miR-148b group and si-CALR group were significantly down-regulated (P < .05). Moreover, compared with anti-miR-con group and Ctrl group, anti-miR-148b group and CALR group cells proliferation and migration were significantly up-regulated (P < .05). In addition, miR-148b was targeted to CALR, and silencing CALR could reverse the inhibitory effect of miR-148b on Schwann cell proliferation and migration. In conclusion, miR-148b can regulate the proliferation and migration of Schwann cells. The mechanism may be related to the targeted negative regulation of CALR, which will provide a basis for targeted therapy of peripheral nerve injury.

Fibroblast growth factor 21 facilitates peripheral nerve regeneration through suppressing oxidative damage and autophagic cell death.

Seeking for effective drugs which are beneficial to facilitating axonal regrowth and elongation after peripheral nerve injury (PNI) has gained extensive attention. Fibroblast growth factor 21 (FGF21) is a metabolic factor that regulates blood glucose and lipid homeostasis. However, there is little concern for the potential protective effect of FGF21 on nerve regeneration after PNI and revealing related molecular mechanisms. Here, we firstly found that exogenous FGF21 administration remarkably promoted functional and morphologic recovery in a rat model of sciatic crush injury, manifesting as persistently improved motor and sensory function, enhanced axonal remyelination and regrowth and accelerated Schwann cells (SCs) proliferation. Furthermore, local FGF21 application attenuated the excessive activation of oxidative stress, which was accompanied with the activation of nuclear factor erythroid‐2‐related factor 2 (Nrf‐2) transcription and extracellular regulated protein kinases (ERK) phosphorylation. We detected FGF21 also suppressed autophagic cell death in SCs. Additionally, treatment with the ERK inhibitor U0126 or autophagy inhibitor 3‐MA partially abolishes anti‐oxidant effect and reduces SCs death. Taken together, these results indicated that the role of FGF21 in remyelination and nerve regeneration after PNI was probably related to inhibit the excessive activation of ERK/Nrf‐2 signalling‐regulated oxidative stress and autophagy‐induced cell death. Overall, our work suggests that FGF21 administration may provide a new therapy for PNI.